Process for the manufacture beta-hydroxy-steroid-ketones

ABSTRACT

WHEN THEY ARE TREATED WITH TRI-N-BUTYLSTANNANE IN AN ORGANIC SOLVENT WHILE IRRADIATING WITH ULTRAVIOLET LIGHT. New types of Beta -hydroxy-steroid-ketones are inter alia 17-oxygenated-7methyl-5-hydroxy-3-oxo-androstanes and 19-nor-androstanes, especially the 7 Alpha -methyl-derivatives and corresponding Delta 1-steroids without the 7-methyl group.   Alpha , Beta -Oxido-steroid-ketones are converted into Beta hydroxy-ketones according to the partial formulas scheme

United States Patent 1 Jeger et al.

PROCESS FOR THE MANUFACTURE OF BETA-HYDRO XY-STEROID- KETONES Inventors: Oskar Jeger, Zollikerberg, Zurich; Hans Ueli Wehrli, Schaffhausen; Kurt Schafiner, Zurich, all of Switzerland Assignee: Ciba-Geigy Corporation, New York,

Filed: Nov. 13, 1970 Appl. No.: 89,527

Related US. Application Data Division of Ser. No. 743,278, July 9, 1968, Pat. No. 3,565,778.

Foreign Application Priority Data July 13, 1967 Switzerland ..l0l08/67 US. Cl. ..260/239.55 R, 260/3974 Int. Cl ..C07c 173/00 Field of Search ..260/397.4, 239.55

References Cited UNITED STATES PATENTS 7/1958 Goldkamp et al ..260/397.4

2/1971 Jeger et al. ..209/158 51 Mar. 27, 1973 OTHER PUBLICATIONS Helv. Chim Acta (1968) No. 4 Vol. 51 Pages 940-944 by Eggert et al.

Primary ExaminerElbert L. Roberts Attorney-Harry Goldsmith, Joseph Kolodny, Bryant W. Brennan and Edward J. Sites ABSTRACT a,B-Oxido-steroid-ketones are converted into B- hydroxy-ketones according to the partial formulas scheme derivatives and corresponding A-steroids without the 7-methyl group.

11 Claims, No Drawings manufacture of ,10-secosteroids.

PROCESS FOR THE MANUFACTURE BETA- I-IYDROXY-STEROID-KETONES I CROSS-REFERENCE TO RELATED APPLICATIONS This is a division of application Ser. No. 743,278, filed July 9,1968, now US. Pat. No. 3,565,778.

BACKGROUND OF THE INVENTION There are already known B-hydroxy-steroid-ketones of the various steroid series with the functional groups in various positions of the cyclopentanopolyhydrophenanthrene or in the side chains, for example, in the pregnane-I7B side chain. Thus, inter alia in German Specification No. 960,200 A-l6-hydroxy' 3,20-diones, containing a free or esterfied 2l-hydroxyl groups have been described. These compounds are pharmacologically active and act as suprarenal hormones. French Pat. No. 1,463,849 discloses S-hydroxy- 3-oxosteroids of the androstane and pregnane series which are suitable for use as starting materials for the process, claimed in that French Specification, for the l-Hydroxy-S-oxosteroids of the pregnane series, especially the lahydroxy derivative of cortisone which has a much higher antiinflammatory effect than cortisone, have been mentioned for instance in Japanese Pat. No. 22,142, and la-hydroxy-derivatives of the Sa-androstane series having a good anabolic-androgenic activity in South African Pat No. 63/5165, and analogous compounds of the Sfl-androstane series, which likewise have a good anabolic-androgenic activity, in Dutch Pat. application No. 6,501 ,292/65. The known methods for the manufacture of such hydroxy-steroid-ketones vary from case to case; thus, the pregnane compounds described in the afore-mentioned German Patent are obtained by adding an arylcarbinol on to the 16,17- double bond of 16,17-unsaturated pregnanes and reductive splitting of the l6-aryloxy group formed. In the case of the above-mentioned French Patent 4,5- oxido-3-ketones are temporarily ketalized and then reduced to S-hydroxy compounds with a complex light metal hydride. The l-hydroxy-3-oxo-androstane compounds of the said South African Patent are likewise obtained by splitting an oxido-3-ketone, namely the epoxide group of a 1,2-oxido-3-ketone, but in this case the reduction is carried out with an alkali or alkaline earth metal in liquid ammonia or in an amine.

SUMMARY OF THE INVENTION The invention provides a new general method for the manufacture of B-hydroxy-steroids which consists in treating with a trialkylstannane an a,B-oxido-steroidketone in a suitable solvent, while being irradiated with ultraviolet light. The invention also comprises new [3- hydroxy steroid ketones of the aor B-androstane series preparable by the new process, and pharmaceutical preparations containing them. The new compounds display androgenic or antiandrogenic activity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the hydroxy-steroid-ketones obtainable with the new process of the invention the ketone group may be in the steroid ring system or in a side chain, and any desired configuration is possible at the various carbon atoms, especially also at those to which the hydroxyl group is attached. In this context the term steroidketone refers to any desired derivative of the cyclopentano-polyhydrophenanthrenes, that is to say not only to the normal steroids but, for example, also to 18- and 19-nor-steroids, A-homo-, B-homo-, A-nor-, B-nor-, C- noror D-homo-steroids.

The steroid starting material used in the new process may be any a,B-oxido-steroid-ketone, for example of the androstane, pregnane, cholane, cholestane, spirostane, cardanolide or furostane series, for instance 4,S-oxido-3-oxo-steroids, 1 ,2-oxido-3-oxo-steroids, 4 ,5oxido-6-oxo-steroids, 5 ,6-oxido-7-oxo-steroids, 9,l l-oxido-l2-oxo-steroids, -oxido-l l-oxo-steroids or 3,4-oxido-2-oxo-steroids, which may contain in other free positions of the oxo-steroids, 4,5-oxido-6-oxo-steroids, 5,6-oxido-7-oxo-steroids, 9,l l-oxidol 2-oxo-steroids, 9,lO-oxido-ll-oxo-steroids or 3,4-oxido-2-oxosteroids, which may contain in other free positions of the steroid skeleton further substituents, and the rings and/or possibly in the side chains, they may contain double bonds.

The starting materials are known or can be manufactured in known manner. For example, a, B-oxido-steroid-ketones are preferably manufactured by epoxidation of the corresponding unsaturated ketones by treatment with hydrogen peroxide in the presence of sodium hydroxide solution or by means of an organic per-acid, such as perphthalic or per-benzoic acid.

The treatment according to this invention with a trialkylstannane with irradiation is carried out in an inert solvent that is stable towards the trialkylstannane and towards the ultraviolet light used for the irradiation, if desired or required with addition of a sensitizer.

Preferred solvents are aliphatic, cycloaliphatic or aromatic hydrocarbons, especially benzene.

As sensitizers there may be used those which are generally employed in photoinduced reactions, for example triphenylene.

A suitable source of light for the irradiation according to this invention is artificial or natural ultraviolet light, preferably ultraviolet light as emitted by mercury high-pressure burners. The irradiation is preferably performed at room temperature.

Preferred trialkylstannanes are tri-lower alkylstannanes, above all tri-n-butylstannane.

Some of the process produces are known and, as mentioned above, they may be used as intermediates in the manufacture of phannacologically active compounds or they possess as such pharmacological properties.

The present invention further includes new B- hydroxy-steroid-k etones, in fact l7-oxygenated 7- methyl-S-hydroxy-3-oxo-androstanes and l9-nor-androstanes, especially 7a-methyl derivatives of this type; also l7-oxygenated A-5-hydroxy-3-oxo-androstenes and l9-nor-androstenes, especially also their 7-methyl derivatives; and l7-oxygenated 5B-hydroxy-3-oxo-l9- nor-androstanes.

This group of new compounds are thus l7-oxygenated 5-hydroxy-3-oxo-compounds of the 501- and SB-androstane and l9-nor-androstane series, which compounds are characterized by the presence of at least one of the following features: the l,2-double bond, a 7-methyl group, or the B-configuration at C together with the l9-nor-structure.

In these compounds the substituent in position 17 is, for example, either an oxo group or a free, etherified or esterified hydroxyl group together with a hydrogen atom or with an unsubstituted or substituted, saturated or unsaturated lower aliphatic hydrocarbon residue.

An esterified hydroxyl group is above all one derived from an organic carboxylic acid of the aliphatic, alicyclic, aromatic or heterocyclic series, especially one that contains one to 18 carbon atoms, for example for mic, acetic, propionic acid, a butyric acid, a valeric such as n-valeric acid, or trimethylacetic, trifluoroacetic acid, a caproic acid such as B-trimethylpropionic acid or diethylacetic acid, oenanthic, caprylic, pelargonic, capric acid, and undecyclic acid, for example undecylenic acid, lauric, myristic, palmitic or stearic acids, for example oleic acid, cyclopropane-, cyclo-pentane-, and cyclohexane-carboxylic acid, cyclopropylmethane-carboxylic, cyclobutylmethanecarboxylic, cyclopentylethane-carboxylic, cyclohexylethanecarboxylic acid, cyclopentyl-, cyclohexylor phenyl-acetic or -propionic acids, benzoic, phenoxyalkanoic acids such as phenoxyacetic acid, dicarboxylic acids such as succinic acid, phthalic, quinolic acid, furan-Z-carboxylic, S-tertiary butylfuran-Z-carboxylic, 5-bromo-furan-Z-carboxylic acid, nicotinic or isonicotinic acid, or from an inorganic acid, for example a phosphoric or sulphuric acid.

An etherified hydroxyl group is especially one derived from an alkanol with one to eight carbon atoms, such as a lower aliphatic alkanol, such as ethanol, methanol, propanol, isopropanol, butyl or amyl alcohol, or from an araliphatic alcohol, especially from a monocyclic aryl-lower aliphatic alcohols such as benzyl alcohol, or from a heterocyclic alcohol such as a-tetrahydropyranol or-furanol.

The lower aliphatic hydrocarbon residue in position 170: may be saturated or unsaturated, unsubstituted, or substituted, for example, by halogen atoms. Preferably, such a residue contains one to four carbon atoms and is in the first place methyl, ethyl, propyl, vinyl, allyl, methallyl, ethinyl, propinyl, trifluoropropinyl or trichloropropinyl.

Specific compounds in these new groups are, for example, 7a-methyl-5B, 17/3-dihydroxy-androstan-3-one and 7a-methyl-5B, l7B-dihydroxy-l9-nor-androstan-3- one and their esters, for example their l7-monoesters or 5B,l7B-diesters, for example the 17-acetates, 7a,l7a-dimethyl-5B, 17B-dihydroxy-androstan-3-one and 7a- 1 7a-dimethyl-5B, 1 7B-dihydroxy- 1 9-nor-androstan-3one and their esters, for example their 5fl,l7B-diesters; also N53,]7B-dihydroxy-androsten- 3-one and N53,]7B-dihydroxy-l9-nor-androsten-3 one and their esters, for example the l7-acetates', 17amethyl-SBJ 7fl-dihydroxyl 9-nor-androstan-3-one and l7a-ethinyl-5Bl 7B-dihydroxyl 9-nor-androstan-3- one.

Another group of the new compounds of the present invention includes the l7-oxygenated A-la-hydroxy- 3-oxo-androstenand -l9-nor-androstenes. The l7-oxygenated residue in position 17 is one of the groups defined above, the ester and ether groups and a lower aliphatic hydrocarbon residue in position 170: preferably likewise being those mentioned above. Special mention deserve, for example, A-la,l7B- dihydroxy-androsten-3-one and its esters, for example l7B-monoesters or 1,17/3-diester, especially the 17- acetate. 5 The new compounds of the present invention and especially the compounds specifically mentioned above are distinguished by their high androgenic and anabolic or an antiandrogenic activity.

Another object of the present invention are the starting materials to be used in the present process for the manufacture of the new N-la-hydroxy-androstenand -l9-nor-androstenes said above, thus the 17-oxygenated A 1la,2a-oxido-3-oxo-androstene and 19- nor-androstene compounds, for example A"-la,2aoxido-l7B-hydroxy-androsten-3one and its esters, such as the 17-acetate, and A-la,2u-oxido-17fl-hydroxyl9-nor-androsten-3-one and its l7-esters, such as the l7B-acetate.

The invention includes also any variant of the process in which an intermediate obtained at any stage is used as starting material and any remaining step/steps is/are carried out, or the process is discontinued at any stage thereof, or in which a starting material is formed under the reaction conditions.

The invention includes also the manufacture of pharmaceutical preparations for use in human or veterinary medicine, which contain the new pharmacologically active substances of the present invention described above as active ingredients, in conjunction or admixture with a pharmaceutical excipient. The excipient used may be an organic or inorganic substance suitable for enteral, for example oral, parenteral or local administration. Suitable excipients are substances that do not react with the new compounds, for example water, gelatin, lactose, starches, magnesium stearate talcum, vegetable oils, benzyl alcohols, gums, polyalkyleneglycols, white petroleum jelly, cholesterol or other, known medicinal excipients. The pharmaceutical preparations may be in solid form, for example tablets, dragees or capsules, or in liquid or semiliquid form solutions, suspensions, emulsions, ointments or creams. These pharmaceutical preparations may be sterilized and/or contain assistants such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may also contain further therapeutically valuable substances. The new compounds may also be used as starting materials in the manufacture of other valuable compounds.

The products of the present invention may also be used as additives to animal fodders.

The following Examples illustrate the invention.

Unless otherwise indicated, the irradiation is performed in benzene in a quartz test tube with a mercury highpressure burner. The infrared spectra and optical rotations have been measured in chloroform and the ultraviolet spectra in ethanol. The irradiated products have been purified by three recrystallizations from acetone-petroleum either in each case.

EXAMPLE 1 mg of 4B,5B-oxido-l7fl-acetoxy-androstan-3one are mixed with 2 ml of tri-n-butylstannane and 8 ml of benzene and the mixture is irradiated for half an hour. The resulting reaction solution is then immediately chromatographed on silica gel, the excess stannane and its reaction products being eluted with benzene. A 4:1- mixture of benzene+ethyl acetate then furnishes 12 mg of unreacted starting material. The later benzene+ethyl acetate lzl-fractions furnish 74 mg of 5fl-hydroxy-l7fiacetoxy-androstan-3-one melting at 176 to 178 C (after 3 recrystallizations). Optical rotation [04],, +27 (0.37). Infrared spectrum: bands at 1028, 1255, 1712 (broad) and 3600 cm.

Example 2 100 mg of 4B,5B-oxido-7oz,l7a-dimethyl-l7ahydroxy-19-nor-androstan-3-one are treated and worked up as described in Example 1.

There are obtained 54 mg of 7a,l7a-dimetbyl-5fl ,17B-dihydroxy-19-nor-androstan-3-one, melting at 206 to 208C. Optical rotation [:15 11(0.50). lnfrared spectrum: bands at 1712 and 3595 cm". In addition 31 mg of starting material are recovered.

EXAMPLE 3 100 gm of 4B,5B-oxido-l7a-methyl-l7B-hydroxy- 19-nor-androstan-3-one are treated as described in Example 1, to yield 71 mg of 17a-methyl-5B,17B-

dihydroxy-l9-nor-androstan-3-one, melting at 181 to 183C. Optical rotation [01],, +7 (0.40). Infrared spectrum: bands at 171 1 and 3595 cm". 24 mg of starting material are recovered.

EXAMPLE 4 100 mg of A-3B-acetoxy-l6a,17a-oxido-pregnen- 20-one are treated as described in Example 1 (irradiation time: 2 /& hours), to yield 23 mg of A -3B-acetoxypregnene-l6,20-dione and 27 mg of A -3B-acetoxyl6a-hydroxy-pregnen-20-one, melting at 168 C. Optical rotation [01],, 7.5 (0.4). Infrared spectrum: bands at 1256, 1703, 1730 and 3605 cm". 30 mg of starting material are recovered.

EXAMPLE-5 100 mg of 1a,2a-oxido-17B-acetoxy-5a-androstan- 3-one are treated as described in Example 1, to yield, inter alia, 44 mg of l7B-acetoxy-5a-androstan-B-one (identified by mixed melting point, infrared spectrum and thin-layer chromatogram) and 39 mg of 1ahydroxy-l7B-acetoxy-5a-androstan-3-one, melting at 239 to 243 C. Optical rotation [a],,=+20 (0.46). lnfrared spectrum: bands at 1250, 1720 and 3600 cm".

Example 6 EXAMPLE 7 200 mg of A-4B,5B-oxido-l7/3-acetoxy-androstem3- one are treated and worked up as described in Example 6. After chromatography on silica gel in benzene+ethy1 acetate mixtures there are obtained:

a. 50 mg of 4B,5B-oxido-17B-acetoxy-androstan-3- one b. 19 mg of A--17B-acetoxy-5,l0-seco-androstene- 3,5-dione; m.p. 215 C; optical rotation [01],, +321 (0.2) infrared spectrum:

1254 and 1720 (broad) cm ultraviolet spectrum:

A 290 my (a 2300, in ethanol) A 302 mu (6 20300 in alcoholic 0.1N-KOH) c. 13.5 mg of testosterone acetate d. 32 mg of O-acetyl-l-dehydrotestosterone e. 33 mg of SB-hydroxy-l713-acetoxy-androstan-3- one f. 54 mg of A-5B-hydroxy-l7B-acetoxy-androstan-3- one m.p. 172 C; optical rotation [0:15 +86 infrared spectrum:

1028,1253,1678,1728, 3590 cm ultraviolet spectrum:

)-,,,,,,,=232 mp. (e=9600).

EXAMPLE 8 180 mg of 4a,5a-oxido-I7B-acetoxy-androstan-3- one are treated as described in Example 1, to yield, inter alia, 59 mg of 17B-acetoxy-5a-androstan-3-one and 82 mg of a crystalline 1:1-mixture of SB-hydroxy- 17B-acetoxy-androstan-3-one and 5a-hydroxy-l7B- acetoxy-adrostan-3-one. We claim:

1. A member selected from the group consisting of a 7-methyl-5-hydroxy-3-oxo-androstane, a A SB-hydroxy-3-oxo-androstene, a 5B-hydroxy-3-oxo-19-nor-androstane, and 19-nor derivatives of the above said androstane and androstene compounds, which compounds have in 17-position a member selected from the group consisting of an oxo group, a free, an esterified and an etherified B-hydroxyl group together with a member selected from the group consisting of hydrogen and an unsubstituted and a halogen-substituted saturated lower aliphatic hydrocarbon radical and a corresponding unsaturated hydrocarbon radical, each of said esterified hydroxy groups being derived from an organic carboxylic acid selected from the group consisting of acids of the aliphatic, the alicyclic, the aromatic and heterocyclic series and having from one to 18 carbon atoms and each of said etherified hydroxy] groups being derived from an alcohol selected from the group consisting of an alkanol having from one to eight carbon atoms, a monocyclic aryl-lower aliphatic alcohol, tetrahydropyranol, and tetrahydrofuranol.

2. A compound according to claim 1 and which is the 7a-methyl-5B,17B-dihydroxy-androstan-3-one.

3. A compound according to claim 11 and which is a member selected from the group consisting of the methyl-513,17B-dihydroxy-l9-nor-androstan-3-one and its l7-acetate.

4. A compound according to claim 11 and which is the 701,17a-dimethyl-5B,17/3-dihydroxy-androstan-3-one.

5. A compound according to claim 1 and which is the 701,1 7a-dimethyl25B,l 7/3-dihydroxy-l 9-nor-androstan- 3-one.

6. A compound according to claim 1 and which is a member selected from the group consisting of the A 5B,l7B-dihydroxy-androsten-3-one and its l7-acetate.

7. A compound according to claim 1, which is the A- 5B,l7B-dihydroxy-l9-nor-androsten-3-one.

8. A compound according to claim 1, which is the l7a-methyl-5B,l7B-dihydroxy-l9-nor-androstan-3- one.

9. A compound according to claim 1, which is the l7a-ethinyl-5fl,l 7B-dihydroxyl 9-nor-androstan-3- one.

10. A member selected from the group consisting of a N-la,2a-oxido-3-oxo-androstene, and -l9-nor-androstene, which compounds have in l7-position a member selected from the group consisting of an oxo group, a free, an esterified and an etherified B-hydroxyl group together with a member selected from the group consisting of hydrogen and an unsubstituted saturated lower aliphatic hydrocarbon radical and a corresponding unsaturated hydrocarbon radical, each of said esterified hydroxy groups being derived from an organic carboxylic acid selected from the group consisting of acids of the aliphatic, the alicyclic, the aromatic and heterocyclic series and having from i to 18 carbon atoms and each of said etherified hydroxyl groups being derived from an alcohol selected from the group consisting of an alkanol having from 1 to 8 carbon atoms, a monocyclic aryllower aliphatic alcohol, tetrahydropyranol and tetrahydrofuranol.

H. A compound according to claim 10 and which is the A-la,2a-oxido-l 7Bacetoxy-androsten-3-one.

2 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,7 3, Dated March 27, 1973 Inventor-(s) OSKAR JEGEILE T AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shownbelow:

Column 7, line 2, after "-dimethyl" delete "2" and insert Signed and sealed this lL th day of May 197b,.

(SEAL) Attest: v

I EDWARD PLFLEICHERJR. C. MARSHALL DANN Attesting Officer Comissioner of Patents 

2. A compound according to claim 1 and which is the 7 Alpha -methyl-5 Beta ,17 Beta -dihydroxy-androstan-3-one.
 3. A compound according to claim 1 and which is a member selected from the group consisting of the 7 Alpha -methyl-5 Beta ,17 Beta -dihydroxy-19-nor-androstan-3-one and its 17-acetate.
 4. A compound according to claim 1 and which is the 7 Alpha ,17 Alpha -dimethyl-5 Beta ,17 Beta -dihydroxy-androstan-3-one.
 5. A compound according to claim 1 and which is the 7 Alpha ,17 Alpha -dimethyl-5 Beta ,17 Beta -dihydroxy-19-nor-androstan-3-one.
 6. A compound according to claim 1 and which is a member selected from the group consisting of the Delta 1-5 Beta ,17 Beta -dihydroxy-androsten-3-one and its 17-acetate.
 7. A compound according to claim 1, which is the Delta 1-5 Beta ,17 Beta -dihydroxy-19-nor-androsten-3-one.
 8. A compound according to claim 1, which is the 17 Alpha -methyl-5 Beta ,17 Beta -dihydroxy-19-nor-androstan-3-one.
 9. A compound according to claim 1, which is the 17 Alpha -ethinyl-5 Beta ,17 Beta -dihydroxy-19-nor-androstan-3-one.
 10. A member selected from the group consisting of a Delta 4-1 Alpha ,2 Alpha -oxido-3-oxo-androstene, and -19-nor-androstene, which compounds have in 17-position a member selected from the group consisting of an oxo group, a free, an esterified and an etherified Beta -hydroxyl group together with a member selected from the group consisting of hydrogen and an unsubstituted saturated lower aliphatic hydrocarbon radical and a corresponding unsaturated hydrocarbon radical, each of said esterified hydroxy groups being derived from an organic carboxylic acid selected from the group consisting of acids of the aliphatic, the alicyclic, the aromatic and heterocyclic series and having from 1 to 18 carbon atoms and each of said etherified hydroxyl groups being derived from an alcohol selecteD from the group consisting of an alkanol having from 1 to 8 carbon atoms, a monocyclic aryllower aliphatic alcohol, tetrahydropyranol and tetrahydrofuranol. --. A compound according to claim 10 and which is the Delta 4-1 Alpha ,2 Alpha -oxido-17 Beta acetoxy-androsten-3-one. 